Project Summary/Abstract Because few non-genetic causes of autism spectrum disorders (ASD) have been studied, this proposal seeks a novel approach to advance our knowledge of the complex etiology of ASD due to exposure to environmental chemicals. Perfluorinated compounds (PFCs) are selected as a chemical class of interest because they are ubiquitous in consumer products such as food packaging, textiles and non-stick coatings on cookware, and have neurologic or neuro-developmental toxicity in experiments with laboratory animals. Also, at least 5 million U.S. people are currently drinking water contaminated with PFCs above a health advisory level. The overall goal of this project is to determine whether exposure to PFCs at an early developmental stage (pregnancy or breastfeeding periods) is associated with risk for ASD. To test our hypothesis, we will utilize two study populations known as ?CHARGE? (CHildhood Autism Risk from Genetics and Environment) and ?MARBLES? (Markers of Autism Risk in Babies ? Learning Early Signs). CHARGE is a population-based case-control study that has enrolled over 1800 index children and their families and thus provides a large number of cases (children with ASD) and controls (typically developing (TD) children) along with blood samples from mothers when their child was 2 to 4 years old. MARBLES is a prospective cohort, enrolling pregnant women who already have a child with ASD and are therefore at high risk for delivering another child with ASD, designed to identify causes and early markers of ASD. From CHARGE that provides a large number of final diagnoses (ASD or TD), we will use direct measures in the mother's blood as a proxy for early life children's exposure during pregnancy and breastfeeding. From MARBLES that provides more accurate time-specific exposure measurements than CHARGE, we will use direct measures in mother's blood collected during pregnancy and breastfeeding periods. While we anticipate that the mother's level in blood when their child was 2 to 4 years old would be a good marker of exposure due to the relatively long elimination half-life of PFCs in the body, we will additionally capitalize on the MARBLES longitudinal biomarker measurements to reconstruct exposure levels during pregnancy and breastfeeding periods for participants in CHARGE and then test the same hypothesis using reconstructed estimates. To achieve our goals, we propose PFC analysis of randomly selected blood samples from mothers of 332 cases (=ASD) and 332 controls (=TD) in CHARGE and 336 blood samples from 112 MARBLES mothers who provided at least one during pregnancy, one during breastfeeding, and one when their child was 2 years old. This project thereby achieves 1) large sample size; 2) precise characterization of PFC exposures during specific developmental periods; and 3) associations of PFCs with cases of ASD that were confirmed by highly trained, research reliable clinicians using gold standard instruments. This study will improve understanding of temporal changes in body burden from pregnancy through the first few years post- partum and provide uniquely high quality data on the role of early PFC exposures in ASD.